Overall SUMMARY/ABSTRACT The overall goal of the Endometrial (Uterine) Cancer SPORE at MD Anderson Cancer Center is to conduct highly innovative translational research for the prevention and treatment of endometrial cancer. Encompassed within this broad overall goal are the following more specific goals: 1) develop novel therapeutic strategies for advanced/recurrent endometrial cancer and aggressive subtypes; 2) promote novel strategies for unmet clinical needs in prevention and conservative therapy of high-risk precancerous lesions and low grade endometrial cancer; 3) incorporate molecular diagnostics into clinical decision-making; and 4) recruit and support new investigators in endometrial cancer research through the Career Enhancement and Developmental Research Programs. Over the last 5 years, our SPORE has led the field with a highly productive translational research team that has helped to define the clinical and molecular heterogeneity of endometrial cancer. This proposal includes 4 translational research projects addressing scientific problems that span the breadth of endometrial cancer heterogeneity in an effort to impact as many patients as possible. Project 1, ?Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer,? includes a phase II trial using the mTOR inhibitor everolimus to improve standard conservative therapy (progestin-eluting intrauterine device) and is paired with innovative molecular profiling and pharmacologic approaches to further advance conservative treatment options. Project 2, ?CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma,? focuses on targeted therapeutics and molecular mechanisms underlying a clinically aggressive subtype of endometrioid endometrial cancer that is driven through beta-catenin mutation and downstream Wnt pathway activation. Project 3, ?EphA2 Targeting in Uterine Carcinoma,? focuses on the therapeutic target, EphA2. EphA2 is overexpressed especially in higher grade endometrioid carcinomas and in serous carcinoma and is associated with poor overall survival. A phase I clinical trial will evaluate the efficacy and toxicity of a novel therapeutic (EPHARNA) that targets EphA2 by delivering short interfering RNA into tumor cells via a neutral liposome nanovehicle. This therapeutic was developed by Project 3 investigators. Project 4, ?A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer,? will evaluate tumor molecular changes from samples procured during a combinatorial trial of PARP and PI3K pathway targeted therapy to identify biomarkers of benefit for patients with endometrial cancer. This is paired with implementing a platform to evaluate mechanisms responsible for adaptive resistance to targeted therapies in order to enable a rational design of improved combination therapies. Four Cores will support these projects- Administrative Core, Pathology Core, Biomarkers Core, and Biostatistics and Bioinformatics Core.